Process for the preparation of 4-amino-3-chloro-5-fluoro-6-(substituted)picolinates

ABSTRACT

4-Amino-3-chloro-5-fluoro-6-(substituted)picolinates are conveniently prepared from 3,4,5,6-tetrachloropicolinonitrile by a series of steps involving fluorine exchange, amination, reaction with hydrazine, halogenation, hydrolysis and esterification, and transition metal assisted coupling.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/356,675 filed Jan. 24, 2012, which claims the benefit of U.S.Provisional Patent Application Ser. No. 61/435,974 filed Jan. 25, 2011.

FIELD OF THE INVENTION

The present invention concerns a process for the preparation of4-amino-3-chloro-5-fluoro-6-(substituted)picolinates. More particularly,the present invention concerns a process for the preparation of4-amino-3-chloro-5-fluoro-6-(substituted)picolinates in which the5-fluoro substituent is introduced by a halogen exchange early in theprocess scheme.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 6,297,197 B1 describes inter alia certain4-amino-3-chloro-5-fluoro-6-(alkoxy or aryloxy)picolinate compounds andtheir use as herbicides. U.S. Pat. Nos. 6,784,137 B2 and 7,314,849 B2describe inter alia certain 4-amino-3-chloro-5-fluoro-6-(aryl)picolinatecompounds and their use as herbicides. U.S. Pat. No. 7,432,227 B2describes inter alia certain4-amino-3-chloro-5-fluoro-6-(alkyl)picolinate compounds and their use asherbicides. Each of these patents describes the manufacture of4-amino-3-chloro-5-fluoropicolinate starting materials by fluorinationof the corresponding 5-unsubstituted picolinates with1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate). It would be advantageous to produce4-amino-3-chloro-5-fluoro-6-(substituted)picolinates without having torely on direct fluorination of the 5-position of the picolinate with anexpensive fluorinating agent like1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate).

SUMMARY OF THE INVENTION

The present invention concerns a process for the preparation of4-amino-3-chloro-5-fluoro-6-(substituted)picolinates from3,4,5,6-tetrachloropicolinonitrile. More particularly, the presentinvention concerns a process for the preparation of a4-amino-3-chloro-5-fluoro-6-(substituted)picolinate of the Formula I

wherein

R represents C₁-C₄ alkyl, cyclopropyl, C₂-C₄ alkenyl or phenylsubstituted with from 1 to 4 substituents independently selected fromhalogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy;and

R¹ represents C₁-C₁₂ alkyl or an unsubstituted or substituted C₇-C₁₁arylalkyl;

which comprises the following steps:

a) fluorinating 3,4,5,6-tetrachloropicolinonitrile (Formula A)

with a source of fluoride ion to produce3-chloro-4,5,6-trifluoropicolinonitrile (Formula B)

b) aminating 3-chloro-4,5,6-trifluoropicolinonitrile (Formula B) withammonia to produce 4-amino-3-chloro-5,6-difluoropicolinonitrile (FormulaC)

c) reacting the fluoro substituent in the 6-position of4-amino-3-chloro-5,6-difluoropicolinonitrile (Formula C) with hydrazineto produce 4-amino-3-chloro-5-fluoro-6-hydrazinopicolinonitrile (FormulaD)

d) halogenating 4-amino-3-chloro-5-fluoro-6-hydrazinopicolinonitrile(Formula D) with a chlorine, bromine or iodine source to produce a4-amino-3-chloro-5-fluoro-6-halopicolinonitrile of Formula E

-   -   wherein L is Br, Cl or I;

e) hydrolyzing and esterifying the4-amino-3-chloro-5-fluoro-6-halopicolinonitrile of Formula E with astrong acid and an alcohol (R¹OH) to produce a4-amino-3-chloro-5-fluoro-6-halopicolinate of Formula F

-   -   wherein L and R¹, are as previously defined; and

f) coupling the 4-amino-3-chloro-5-fluoro-6-halopicolinate of Formula Fwith an aryl, alkyl or alkenyl metal compound of the Formula GR-Met  G

-   -   wherein R is as previously defined and Met represents,        Zn-halide, Zn—R, tri-(C₁-C₄ alkyl)tin, copper, or B(OR²)(OR³),        where R² and R³ are independent of one another, hydrogen, C₁-C₄        alkyl, or when taken together form an ethylene or propylene        group in the presence of a transition metal catalyst to produce        the 4-amino-3-chloro-5-fluoro-6-(substituted)picolinate of        Formula I.

The steps a) through f) may be performed in the order listed, asdepicted in Scheme I, or some of the steps can be rearranged intodifferent orders as allowed by the compatibility of the chemistry. Forexample, the coupling of step f) may be performed prior to thehydrolysis and esterification of step e).

An additional aspect of the invention concerns an improved method ofincreasing the amount of recoverable3-chloro-4,5,6-trifluoropicolinonitrile (Formula B)

prepared from fluorinating 3,4,5,6-tetrachloropicolinonitrile (FormulaA)

with a source of fluoride ion wherein the improvement comprises thesteps of:

i) isolating the over-fluorinated 3,4,5,6-tetrafluoropicolinonitrile (H)

by-product from fluorinating 3,4,5,6-tetrachloropicolinonitrile;

ii) reacting the isolated 3,4,5,6-tetrafluoropicolinonitrile (H) (a)with lithium chloride (LiCl), (b) with3,4,5,6-tetrachloropicolinonitrile (Formula A) in the presence of aphase-transfer catalyst or (c) with a combination of LiCl and3,4,5,6-tetrachloropicolinonitrile to produce a mixture consistingpredominantly of 3,4,5,6-tetrachloropicolinonitrile,monofluoro-trichloropicolinonitrile anddifluoro-dichloropicolinonitrile; and

iii) recycling the mixture consisting predominantly of3,4,5,6-tetrachloropicolinonitrile, monofluoro-trichloropicolinonitrileand difluoro-dichloropicolinonitriles to the fluorination reactionpreparing 3-chloro-4,5,6-trifluoropicolinonitrile (Formula B).

Another aspect of the present invention is the novel intermediateproduced during the present process, viz., the compound:

DETAILED DESCRIPTION OF THE INVENTION

The terms “alkyl,” “alkenyl” and “alkynyl,” as well as derivative termssuch as “alkoxy,” “acyl,” “alkylthio” and “alkylsulfonyl,” as usedherein, include within their scope straight chain, branched chain andcyclic moieties. Unless specifically stated otherwise, each may beunsubstituted or substituted with one or more substituents selected frombut not limited to halogen, hydroxy, alkoxy, alkylthio, C₁-C₆ acyl,formyl, cyano, aryloxy or aryl, provided that the substituents aresterically compatible and the rules of chemical bonding and strainenergy are satisfied. The terms “alkenyl” and “alkynyl” are intended toinclude one or more unsaturated bonds.

The term “arylalkyl,” as used herein, refers to a phenyl substitutedalkyl group having a total of 7 to 11 carbon atoms, such as benzyl(—CH₂C₆H₅), 2-methylnaphthyl (—CH₂C₁₀H₇) and 1- or 2-phenethyl(—CH₂CH₂C₆H₅ or —CH(CH₃)C₆H₅). The phenyl group may itself beunsubstituted or substituted with one or more substituents independentlyselected from halogen, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxy,halogenated C₁-C₆ alkyl, halogenated C₁-C₆ alkoxy, C₁-C₆ alkylthio,C(O)OC₁-C₆alkyl, or where two adjacent substituents are taken togetheras —O(CH₂)_(n)O— wherein n=1 or 2, provided that the substituents aresterically compatible and the rules of chemical bonding and strainenergy are satisfied.

Unless specifically limited otherwise, the term “halogen,” as well asderivative terms such as “halo,” refers to fluorine, chlorine, bromineand iodine.

The phenyl groups substituted with from 1 to 4 substituentsindependently selected from halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy or C₁-C₄ haloalkoxy may be of any orientation, but 4-substitutedphenyl, 2,4-disubstituted phenyl, 2,3,4-trisubstituted phenyl,2,4,5-trisubstituted phenyl, and 2,3,4,6-tetrasubstituted phenyl isomersare preferred.

The 4-amino-3-chloro-5-fluoro-6-(substituted)picolinates are preparedfrom 3,4,5,6-tetrachloropicolinonitriles by a series of steps involvingfluorine exchange, amination, reaction with hydrazine, halogenation,hydrolysis, esterification and transition metal assisted coupling. Theindividual steps may be performed in different sequences.

The 3,4,5,6-tetrachloropicolinonitrile starting material is a knowncompound and is commercially available.

In the fluoride exchange reaction, the fluorinated picolinonitrile isprepared by reacting the corresponding chlorinated picolinonitrile withapproximately one equivalent of fluoride ion source for each ringchlorine substituent to be exchanged.

Typical fluoride ion sources are alkali metal fluorides which includesodium fluoride (NaF), potassium fluoride (KF) and cesium fluoride(CsF), with KF and CsF being preferred. Quaternary alkyl or arylammonium or phosphonium fluoride may also be used as a fluoride sourceor as an additive. Preferably, the reaction is carried out in a polaraprotic solvent or reaction medium such as, dimethylsulfoxide (DMSO),N-methylpyrrolidinone (NMP), N,N-dimethylformamide (DMF),hexamethylphosphoramide (HMPA) or sulfolane. The temperature at whichthe reaction is conducted is not critical but usually is from about 60°C. to about 180° C. and preferably from about 70° C. to about 80° C.Depending upon which solvent is employed in a particular reaction, theoptimum temperature will vary. Generally speaking, the lower thetemperature the slower the reaction will proceed. The present reactionis typically conducted in the presence of vigorous agitation sufficientto maintain an essentially uniformly dispersed mixture of the reactants.

In conducting the fluorination reaction, neither the rate nor the orderof addition of the reactants is critical. Usually, the solvent andalkali metal fluoride are mixed before the chlorinated picolinonitrileis added to the reaction mixture. A typical reaction generally requiresfrom about 2 to about 100 hours, preferably from 3 to 6 hours and isusually conducted at ambient atmospheric pressure.

While the exact amount of reactants is not critical, it is preferred toemploy an amount of alkali metal fluoride which will supply at least anequimolar amount of fluorine atoms based on the number of chlorine atomsto be exchanged in the starting material, i.e., at least an equimolaramount of alkali metal fluoride. After the reaction is completed thedesired product is recovered by employing standard separation andpurification techniques such as distillation, crystallization orchromatography.

In a typical fluoride exchange, a mixture of products is obtained,including a significant amount of the over-fluorinated by-product3,4,5,6-tetrafluoropicolinonitrile (Formula H).

The ultimate yield of the desired3-chloro-4,5,6-trifluoropicolinonitrile can be enhanced by isolating theover-fluorinated by-product 3,4,5,6-tetrafluoropicolinonitrile andrecycling it to produce intermediates that can be subjected to thefluoride exchange reaction. This can be accomplished in several ways.Reaction of 3,4,5,6-tetrafluoropicolinonitrile with LiCl or reaction of3,4,5,6-tetrafluoropicolinonitrile with an excess of3,4,5,6-tetrachloropicolinonitrile or a combination of both, with orwithout solvents, leads to mixtures of chloro-fluoropicolinonitrileswhere the 3-chloro isomers are useful as a starting material to form thedesired product. Thus 3,4,5,6-tetrafluoropicolinonitrile can be heatedwith excess LiCl to produce a mixture of predominately3,4,5-trichloro-6-fluoropicolinonitrile and tetrachloropicolinonitrile.In another technique, reaction of the isolated3,4,5,6-tetrafluoropicolinonitrile with an excess of3,4,5,6-tetrachloropicolinonitrile in the presence of a phase-transfercatalyst produces a mixture consisting predominantly ofmonofluoro-trichloropicolinonitriles anddifluoro-dichloropicolinonitriles. Finally, equal mixtures of isolated3,4,5,6-tetrafluoropicolinonitrile and3,4,5,6-tetrachloropicolinonitrile in the presence of a phase-transfercatalyst and from about 1 to about 3 equivalents of LiCl produces amixture of predominately 3,4,5-trichloro-6-fluoropicolinonitrile and3,4,5,6-tetrachloropicolinonitrile. These mixtures, consistingpredominantly of monofluoro-trichloropicolinonitriles and/ordifluoro-dichloropicolinonitriles, are useful in a fluorination reactionusing an alkali metal fluoride to prepare3-chloro-4,5,6-trifluoropicolinonitrile from3,4,5,6-tetrafluoropicolinonitrile.

In a reverse halogen exchange reaction,3,4,5,6-tetrafluoropicolinonitrile is heated with from about 5 to about10 equivalents of LiCl, preferably with about 6 equivalents to produce amixture of 4,5-dichloro-3,6-difluoropicolinonitrile (3,6-F₂—PN),6-fluoro-3,4,5-trichloropicolinonitrile (6-F—PN) and3,4,5,6-tetrachloropicolinonitrile (Cl₄—PN). The reaction can be carriedout neat or in a polar aprotic solvent or reaction medium such as, DMSO,NMP, DMF, HMPA or sulfolane. It is often convenient to conduct thereaction in a solvent. The temperature at which the reaction isconducted is not critical but usually is from about 80° C. to about 200°C. and preferably from about 100° C. to about 150° C.

About 90% or more of the mixture is useful to form3-chloro-4,5,6-trifluoropicolinonitrile by recycling the mixture throughthe fluorine exchange reaction.

In the metathesis reaction in which fluoro and chloro groups areinterchanged, the 3,4,5,6-tetrafluoropicolinonitrile is reacted withfrom 1 to about 3 equivalents of 3,4,5,6-tetrachloropicolinonitrile,preferably with about 2 equivalents of3,4,5,6-tetrachloropicolinonitrile. The reaction can be carried out neator in a polar aprotic solvent or reaction medium such as, DMSO, NMP,DMF, HMPA or sulfolane. It is often convenient to conduct the reactionwithout a solvent. The metathesis reaction is conducted in the presenceof an additive. Additives include (a) quaternary phosphonium saltscontaining 10 or more carbon atoms and (b) macrocyclic polyetherscommonly known as crown ethers. Suitable crown ether catalysts include,but are not limited to, 18-crown-6; dicyclohexano-18-crown-6;dibenzo-18-crown-6; 15-crown-S. Suitable quaternary phosphonium saltsinclude the tetra-n-alkylphosphonium salts which are especiallypreferred. The temperature at which the reaction is conducted is notcritical but usually is from about 80° C. to about 200° C. andpreferably from about 150° C. to about 180° C.

In a typical metathesis reaction, for example, in which 1 equivalent of3,4,5,6-tetrafluoropicolinonitrile is allowed to react with about 2equivalents of 3,4,5,6-tetrachloropicolinonitrile, the following mixtureof isomers can be obtained: 3,4,5,6-tetrachloropicolinonitrile (Cl₄—PN),3,5-dichloro-4,6-difluoropicolinonitrile (4,6-F₂—PN),3,4-dichloro-5,6-difluoropicolinonitrile (5,6-F₂—PN),4,5-dichloro-3,6-difluoropicolinonitrile (3,6-F₂—PN),6-fluoro-3,4,5-trichloropicolinonitrile (6-F—PN) and4-fluoro-3,5,6-trichloropicolinonitrile (4-F—PN).

About 80% of the mixture is useful to form3-chloro-4,5,6-trifluoropicolinonitrile by recycling the mixture throughthe fluorine exchange reaction.

In the combination of reverse halogen exchange reaction and themetathesis reactions, the 3,4,5,6-tetrafluoropicolinonitrile is allowedto react with from 1 to about 3 equivalents of3,4,5,6-tetrachloropicolinonitrile, preferably with about 1 equivalentof 3,4,5,6-tetrachloropicolinonitrile and with from about 1 to about 4equivalents of LiCl, preferably with from about 1.5 to about 2.5equivalents. The reaction can be carried out neat or in a polar aproticsolvent or reaction medium such as, DMSO, NMP, DMF, HMPA or sulfolane.It is often convenient to conduct the reaction without a solvent. Themetathesis reaction is conducted in the presence of an additive.Additives include (a) quaternary phosphonium salts containing 10 or morecarbon atoms and (b) macrocyclic polyethers commonly known as crownethers. Suitable crown ether catalysts include, but are not limited to,18-crown-6; dicyclohexano-18-crown-6; dibenzo-18-crown-6; 15-crown-S.Suitable quaternary phosphonium salts include thetetra-n-alkylphosphonium salts which are especially preferred. Thetemperature at which the reaction is conducted is not critical butusually is from about 80° C. to about 200° C. and preferably from about150° C. to about 180° C.

In a typical combination of the reverse halogen exchange and metathesisreactions, for example, 1 equivalent of3,4,5,6-tetrafluoropicolinonitrile is allowed to react with about 1equivalent of 3,4,5,6-tetrachloropicolinonitrile and 1.5 equivalents ofLiCl, and the following mixture of isomers can be obtained:

About 92% of the mixture is useful to form3-chloro-4,5,6-trifluoropicolinonitrile by recycling the mixture throughthe fluorine exchange reaction.

In the amination reaction, the 4-fluoropicolinonitrile is allowed toreact with ammonia to replace the fluorine atom with an amino group.

While only a stoichiometric amount of ammonia is required, it is oftenconvenient to use a large excess of ammonia. It is often convenient touse the ammonia as both the reactant and the base to neutralize thehydrogen fluoride (HF) produced in the reaction. Alternatively, theammonia can be in solution form, such as an aqueous solution of ammoniumhydroxide. The reaction is carried out without a solvent or in an inertsolvent. If a solvent is used, inert solvents include, but are notlimited to, alcohols, ethers, esters, ketones, DMSO and aromaticsolvents. The temperature at which the reaction is conducted is notcritical but usually is from about 0° C. to about 45° C. and preferablyfrom about 10° C. to about 30° C.

A typical reaction generally requires from about 0.5 to about 5 hoursand is usually conducted at ambient atmospheric pressure. The desiredproduct is recovered by employing standard separation and purificationtechniques.

In the reaction with hydrazine, the 6-fluoropicolinonitrile is allowedto react with hydrazine to replace the fluorine atom with a hydrazinogroup.

While only a stoichiometric amount of hydrazine is required, it is oftenconvenient to use an excess of the hydrazine as both a reactant and as abase to neutralize the HF formed in the reaction. The hydrazine ispreferably the monohydrate. The reaction is carried out in an inertpolar solvent such as DMSO, DMF, NMP, acetonitrile, a chlorinatedsolvent, an ether, tetrahydrofuran (THF) or an alcohol. A mixture ofDMSO and THF is preferred. The temperature at which the reaction isconducted is not critical but usually is from about ambient temperatureto about 150° C. and preferably from about 35° C. to about 70° C.

In conducting the reaction with hydrazine, the hydrazine is dissolved inthe solvent and 6-fluoropicolinonitrile is added to the reactionmixture. A typical reaction generally requires from about 0.5 to about 5hours and is usually conducted at atmospheric pressure. The desiredproduct is recovered by employing standard separation and purificationtechniques. The compounds can be easily isolated by dilution of thereaction mixture with acetonitrile followed by filtration.

In the halogenation reaction, the 6-halopicolinonitrile is prepared byreacting the corresponding 6-hydrazinopicolinonitrile with at least oneequivalent of a brominating, chlorinating or iodinating agent.

Suitable iodinating, chlorinating and brominating agents include but arenot limited to iodine, iodine monochloride, chlorine, bromine, sulfurylchloride and sulfuryl bromide. While only a stoichiometric amount ofhalogenating agent is required, it is often convenient to use an excessof the halogenating agent. The reaction is carried out in an inertaprotic solvent. A variety of solvents may be used such as chlorinatedsolvents, acetonitrile, DMSO, dioxane, DMF, and water. It is oftenpreferable to use a chlorinated solvent. The temperature at which thereaction is conducted is not critical but usually is from about ambienttemperature to about 100° C. and preferably from about ambienttemperature to about 50° C.

In conducting the halogenation reaction, the 6-hydrazinopicolinonitrileis dissolved or suspended in the solvent and the halogenating agent isadded to the reaction mixture. A typical reaction generally requiresfrom about 0.5 to about 24 hours. The desired product is recovered byemploying standard separation and purification techniques.

In the hydrolysis and esterification reactions, the picolinonitrile isallowed to react with an alcohol (R¹OH) in the presence of a Lewis orBronsted acid.

Bronsted acids include but are not limited to acids such as hydrochloricacid, sulfuric acid and phosphoric acid. Lewis acids include borontrifluoride, titanium tetrahalides, titanium tetraalkoxides, zinchalides, tin halides and phosphorus and antimony pentafluorides. Acidssuch as sulfuric acid or phosphoric acid are typically employed instoichiometric amounts. The reaction is carried out in the C₁-C₁₂ alkylalcohol or an unsubstituted or substituted C₇-C₁₁ arylalkyl alcohol ofthe desired ester. The reaction is conveniently conducted in a sealedreactor if the reaction temperature is above the boiling point of thealcohol solvent. In conducting the esterification, the picolinonitrile,or the hydrolysis intermediate picolinamide, is added to a mixture ofthe alcohol and acid. Although the temperature of the reaction is notcritical, it is often heated to from about 80° C. to about 140° C. forabout 2 to about 24 hours, preferably from about 100° C. to about 120°C. for about 6 to about 8 hours. The desired product is recovered byemploying standard separation and purification techniques.

In the coupling reaction, a 6-halopicolinate is allowed to react with anaryl, alkyl or alkenyl metal compound where the metal is a Zn-halide,Zn—R, tri-(C₁-C₄ alkyl)tin, copper, or B(OR²)(OR³), where R² and R³ areindependent of one another, hydrogen, C₁-C₄ alkyl, or when takentogether form an ethylene or propylene group, in the presence of atransition metal catalyst.

“Catalyst” is a transition metal catalyst, in particular a palladiumcatalyst such as palladium diacetate ordichlorobis(triphenylphosphine)palladium(II), or a nickel catalyst suchas nickel(II) acetylacetonate ordichlorobis(triphenylphosphine)nickel(II). In addition, catalysts can beprepared in situ from metal salts and ligands, such as palladium(II)acetate and triphenylphosphine or nickel(II) chloride andtriphenylphosphine. These in situ catalysts can be prepared by priorreaction of metal salt and ligand, followed by addition to the reactionmixture, or by separate addition of the metal salt and ligand directlyto the reaction mixture.

Typically, coupling reactions are carried out in the absence of oxygenusing an inert gas, such as nitrogen or argon. Techniques used toexclude oxygen from coupling reaction mixtures, such as sparging withinert gas, are well known to those skilled in the art. Examples of suchtechniques are described in The Manipulation of Air-Sensitive Compounds,2^(nd) ed., D. F. Shriver, M. A. Drezdzon; Wiley-Interscience, 1986.Sub-stoichiometric amounts of a catalyst are used, typically from about0.0001 equivalents to 0.1 equivalents. Additional amounts of ligand mayoptionally be added to increase catalyst stability and activity. Inaddition, additives such as sodium carbonate, potassium carbonate,potassium fluoride, cesium fluoride and sodium fluoride are typicallyadded to the coupling reaction. The coupling reaction generally requiresfrom about 1 to about 5 equivalents of such additive, preferably from 1to 2 equivalents. Water may optionally be added to the coupling reactionto increase the solubility of these additives. The coupling reactiongenerally requires from about 1 to about 3 equivalents of an aryl, alkylor alkenyl metal compound, preferably from 1 to 1.5 equivalents. Thereaction is carried out in an inert solvent, such as toluene, THF,dioxane or acetonitrile. The temperature at which the reaction isconducted is not critical but usually is from about 25° C. to about 150°C. and preferably from about 50° C. to about 125° C. A typical reactiongenerally requires from about 0.5 to about 24 hours. No particular orderof addition of reactants is typically required. It is oftenoperationally simpler to combine all reactants except the catalyst andthen deoxygenate the reaction solution. Following deoxygenation, thecatalyst can be added to commence the coupling reaction.

When the Met portion of the aryl, alkyl or alkenyl metal compound is aZn-halide, Zn—R or copper, protection of reactive functional groups maybe necessary. For example, if an amino substituent (—NHR or —NH₂) ispresent, protection of these reactive groups may be required. A varietyof groups are known in the art for protection of amino groups fromreaction with organometallic reagents. Examples of such protectinggroups are described in Protective Groups in Organic Synthesis, 3^(rd)ed., T. W. Greene, P. G. M. Wuts, Eds.; Wiley-Interscience, 1999. Thechoice of which metal to use in R-Met is influenced by a number offactors, such as cost, stability, reactivity and the need to protectreactive functional groups.

The products obtained by any of these processes, can be recovered byconventional means, such as evaporation or extraction, and can bepurified by standard procedures, such as by recrystallization orchromatography.

The following examples are presented to illustrate the invention.

EXAMPLES Fluorine Exchange Example 1a3-Chloro-4,5,6-trifluoropicolinonitrile

A 5-liter (L) mechanically stirred flask under nitrogen was charged withDMSO (3820 milliliters (mL)), powdered potassium carbonate (K₂CO₃; 42grams (g)) and finely milled cesium fluoride (CsF; 1510 g). DMSO(approximately 1 L) was removed by distillation at 75-80° C. (3.5 mmHg,0.46 kPa). The slurry was cooled to 55° C. under nitrogen before theaddition of finely milled 3,4,5,6-tetrachloropicolinonitrile (685 g).The addition was conducted over a 15 minute (min) period while coolingto keep the reaction temperature below 74° C. The temperature was heldat 65-70° C. under a slow nitrogen stream for 4 hours (h). The reactionmixture was cooled to about 40-50° C. and poured into a mixture of icewater (H₂O; 15 L) and diethyl ether (Et₂O; 3 L). After the organic phasewas separated, the aqueous phase was extracted with Et₂O (2×2 L). Theorganic extracts were combined, dried over magnesium sulfate (MgSO₄),filtered and concentrated by distillation at atmospheric pressure togive the crude product mixture (469 g) as light brown oil. This oil wascombined with additional material prepared similarly to give a total of1669 g of crude product. This oil was distilled under vacuum using a 30tray Oldershaw column at a temperature range between 80-90° C. withfractions collected at 63, 13 and 2 mm Hg (8.4, 1.7 and 0.27 kPa). Thematerial collected at 13 mm gave 457 grams (22% yield) of a solid thatwas a 93/7 mixture of two chlorotrifluoropicolinonitriles. This solidwas recrystallized at 5° C. from a mixture of hexane (420 g) and Et₂O togive 3-chloro-4,5,6-trifluoropicolinonitrile (354 grams, 98% purity) asfine white needles. A small sample was recrystallized a second time to99.7% purity by gas chromatography (GC): mp 41.5-43° C.; ¹⁹F NMR (376MHz, CDCl₃) 6-78.1 (t, J_(F-F)=23.1 Hz, F6), −114.2 (dd, J_(F-F)=18.5,22.5 Hz, F4), −149.3 (dd, J_(F-F)=18.2, 22.6 Hz, F5); ¹³C{¹H} NMR (101MHz, CDCl₃) δ 154.5 (ddd, J_(F-C)=270, 11, 7 Hz, C4), 151.3 (ddd,J_(F-C)=247, 13, 5 Hz, C6), 138.0 (ddd, J_(F-C)=279, 31, 13 Hz, C5),124.7 (ddd, J_(F-C)=16, 6, 2 Hz, C3), 124.4 (ddd, J_(F-C)=16, 7, 2 Hz,C2), 112.2 (s, CN); EIMS m/z 192 ([M]⁺). Anal. Calcd for C₆ClF₃N₂: C,37.43; N, 14.55. Found: C, 36.91; N, 14.25.

The first part of the distillation (63 mm Hg, 8.4 kPa) gave pure3,4,5,6-tetrafluoropicolinonitrile (525 g, 24%) as a colorless oil: ¹⁹FNMR (376 MHz, CDCl₃) δ −77.6 (t, J_(F-F)=23.8 Hz, F6), −133.7 (q,J_(F-F)=18.8 Hz, F4), −134.2 (ddd, J_(F-F)=24.2, 18.6, 10.1 Hz, F3),−145.3 (ddd, J_(F-F)=24.1, 18.2, 10.2 Hz, F5); ¹³C{¹H} NMR (101 MHz,CDCl₃) δ 150.4 (dm, J_(F-C)=272 Hz, C3), 148.5 (ddd, J_(F-C)=245, 12, 4Hz, C6), 147.3 (dm, J_(F-C)=270 Hz, C4), 138.6 (ddd, J_(F-C)=280, 33, 11Hz, C5), 113.4 (m, C2), 110.20 (s, CN).

The third part of the distillation (2 mm Hg, 0.27 kPa) gave3,5-dichloro-4,6-difluoropicolinonitrile (48 g, 98% purity) as a whitesolid: mp 78-79° C.; ¹⁹F NMR (376 MHz, CDCl₃) δ −63.65 (d, J_(RF)=18.7Hz, F6), −92.52 (d, J_(F-F)=18.5 Hz, F4); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ162.6 (dd, J_(F-C)=269, 6 Hz, C4), 157.8 (dd, J_(F-C)=245, 5 Hz, C6),127.6 (dd, J_(F-C)=17, 3 Hz, C3), 123.5 (dd, J_(F-C)=18, 6 Hz, C2),112.4 (dd, J_(F-C)=36, 21 Hz, C5), 112.3 (CN).

Example 1b Reverse Halogen Exchange Reaction of3,4,5,6-tetrafluoropicolinonitrile with Lithium Chloride

A mixture of 3,4,5,6-tetrafluoropicolinonitrile (17 g, 0.1 mole (mol))and dry LiCl (25.4 g, 0.6 mol) was heated in dry DMSO (200 mL). Thereaction was monitored by GC analysis of aliquots extracted into Et₂Ofrom H₂O. Initially the reaction was heated to 120° C. and all of theLiCl dissolved. After 5 min at 120° C., all of the starting material andthe chlorotrifluoro-PN isomers were consumed to give a mixture of3,6-F₂—PN (83%) and 6-F—PN (14%). The temperature of the reaction wasraised to 135° C. and after a total of 75 min was analyzed by GC. Themixture was determined to be a 8:80:12 mixture of3,6-F₂—PN/6-F—PN/Cl₄—PN.

Example 1ca Metathesis of 3,4,5,6-tetrafluoropicolinonitrile

A mixture of 3,4,5,6-tetrachloropicolinonitrile (16.1 g, 66 millimoles(mmol)) and 3,4,5,6-tetrafluoropicolinonitrile (5.9 g, 33 mmol) wereheated to 160° C. under nitrogen to form a solution. To this stirredsolution was added tetrabutyl phosphonium chloride (Bu₄PCl; 0.36 g, 1.2mmol), and the solution was held at 160° C. for 1 h. An aliquot wasdissolved in methylene chloride (CH₂Cl₂) and passed through a short padof silica gel before GC analysis. The profile of halogenatedpicolinonitriles was: 11.2% Cl₄—PN; 11.3% 4,6-F₂—PN; 2.3% 5,6-F₂—PN; 19%3,6-F₂—PN; 52.6% 6-F—PN and 3.6% 4-F—PN. About 80% of the mixture isuseful in the halogen exchange reaction to produce3-chloro-4,5,6-trifluoropicolinonitrile.

Example 1cb Recycle from Metathesis of3,4,5,6-tetrafluoropicolinonitrile

A reaction flask fitted with a short path distillation head was chargedwith finely milled CsF (35.1 g, 0.23 mol) and dry DMSO (175 mL). Thereactor was stirred and heated to 70-75° C. under vacuum (0.1 mm) untilDMSO (75 mL) was distilled off. This slurry was cooled to 50° C. undernitrogen, and the molten reaction mixture from above (21.7 g) was added.The reaction mixture was heated to 70° C. for 2.5 h with good stirring.A diethyl ether extract of an aliquot added to water was checked by GCand found to contain: 61% 3,4,5,6-tetrafluoropicolinonitrile; 31%3-chloro-4,5,6-trifluoropicolinonitrile; 3.4%5-chloro-3,5,6-trifluoropicolinonitrile and 4.8%3,5-dichloro-4,6-difluoropicolinonitrile. This compares favorably to atypical crude GC purity of 38-42% when a similar reaction is conductedstarting with pure 3,4,5,6-tetrachloropicolinonitrile.

Example 1d LiCl Assisted Metathesis of3,4,5,6-tetrafluoropicolinonitrile

A mixture of 3,4,5,6-tetrachloropicolinonitrile (12.2 g, 50 mmol) and3,4,5,6-tetrafluoropicolinonitrile (8.8 g, 50 mmol) were heated to 160°C. under nitrogen to achieve a clear solution. To this was added Bu₄PCl(0.36 g, 1.2 mmol). The reaction solution was held at 160° C. for 15 minbefore adding dry LiCl (4.2 g, 0.1 mol). After 60 min more LiCl (2.2 g,50 mmol) was added, and the reaction mixture was stirred for 11 h. GCanalysis of an ether extract from water showed an 8:75:17 mixture of3,6-F₂—PN/6-F—PN/Cl₄—PN.

Amination

Example 2 4-Amino-3-chloro-5,6-difluoropicolinonitrile

A solution of 3-chloro-4,5,6-trifluoropicolinonitrile (200 g) in ethylacetate (EtOAc; 3 L) was cooled to 10° C. To this was slowly added 14%aqueous ammonium hydroxide (NH₄OH; 1296 g) keeping the temperaturebetween 18-23° C. The aqueous solution was separated from the organicsolution. The organic phase was washed sequentially with a 50/50solution of aqueous saturated NaCl and water (500 mL) and saturated NaClsolution (250 mL). The organic phase was concentrated under vacuum at50° C. to about 500 mL volume as the product crystallized out. To thisslurry was added heptane (1 L), and the remaining EtOAc was removedunder vacuum to give the final slurry. The solids were collected byfiltration. This solid was washed with pentane and dried under vacuum togive 4-amino-3-chloro-5,6-difluoropicolinonitrile (173.8 g, 90%, 99.6%purity) as a white crystalline solid: mp 190-191.5° C.; ¹³C{¹H} NMR (101MHz, DMSO-d₆) δ 150.03 (dd, J=232.4, 12.5 Hz, C6), 144.29 (dd, J=11.4,6.9 Hz, C4), 133.72 (dd, J=257.9, 30.8 Hz, C5), 122.14 (dd, J=19.6, 4.9Hz, C2), 119.31 (s, C3), 114.25 (s, CN); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−91.24 (d, J=24.2 Hz), −154.97 (d, J=24.2 Hz); EIMS m/z 189 ([M]⁺).Anal. Calcd for C₆H₂ClF₂N₃: C, 38.02; H, 1.06; N, 22.17. Found: C.37.91; H, 1.00; 22.02.

Reaction with Hydrazine

Example 3 4-Amino-3-chloro-5-fluoro-6-hydrazinopicolinonitrile

To a solution of hydrazine hydrate (3.9 g, 78 mmol) in THF (15 mL) andDMSO (10 mL) was added 4-amino-3-chloro-5,6-difluoropicolinonitrile (5g, 26 mmol) as a solution in DMSO (5 mL). This solution was heated to65° C. for 45 min, cooled and diluted with acetonitrile (30 mL) toprecipitate the product as a light tan solid. This solid was dried undervacuum at 40° C. for 3 h to give4-amino-3-chloro-5-fluoro-6-hydrazinopicolinonitrile (5.1 g, 98%): mp215-220° C. dec; ¹H NMR (400 MHz, DMSO-d₆) 7.9 (br, 1H), 6.5 (br, 2H),4.0 (br, 2H); ¹³C {1H} NMR (101 MHz, DMSO-d₆) δ 149.34 (d, J=10.5 Hz,C6), 138.28 (d, J=11.6 Hz, C4), 133.81 (d, J=251.6 Hz, C5), 123.74 (d,J=5.3 Hz, C2), 115.87 (s, C3), 112.57 (s, CN); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −154.6; ESIMS m/z 203 ([M+H]⁺). Anal. Calcd for C₆H₅ClFN₅: C,35.75; H, 2.50; N, 34.74. Found: C, 35.97; H, 2.70: N, 35.01.

Halogenation

Example 4 4-Amino-3,6-dichloro-5-fluoropicolinonitrile

To a suspension of 4-amino-3-chloro-5-fluoro-6-hydrazinylpicolinonitrile(9.04 g, 44.8 mmol) in CH₂Cl₂ (150 mL) was added sulfuryl chloride (7.20mL, 89 mmol). The mixture was stirred at room temperature for 40 h. Thesolvent was removed under reduced pressure, and the residue waspartitioned with saturated aqueous sodium bicarbonate (NaHCO₃) andEtOAc. The organic phase was separated, dried over Na₂SO₄, and filtered.The solution was concentrated and the residue was purified by silica gelchromatography to give the product (7.01 g, 76%) as an off-white solid:¹H NMR (300 MHz, DMSO-d₆) δ 7.55 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ143.26 (d, J=259.2 Hz, C5), 142.69 (d, J=14.0 Hz, C4), 135.53 (d, J=17.6Hz. C6), 126.07 (d, J=4.4 Hz, C2), 120.14 (d, J=4.3 Hz, C3), 114.36 (s,CN); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −132.30 (s); ESIMS m/z 203 ([M+H]⁺),206.

Hydrolysis and Esterification

Example 5 Methyl 4-amino-3,6-dichloro-5-fluoropicolinate

Concentrated sulfuric acid (2.0 mL, 37.5 mmol) was added slowly tomethyl alcohol (8 mL) with cooling. Then4-amino-3,6-dichloro-5-fluoropicolinonitrile (0.20 g, 0.97 mmol) wasadded to the solution, and the mixture was stirred at reflux for 29 h.The solvent was removed under vacuum, and the residue was poured intoice and stirred for 15 min. The product was extracted with EtOAc (3×).The organic extracts were combined, washed with brine, dried over MgSO₄,filtered, and purified by silica gel column to give methyl4-amino-3,6-dichloro-5-fluoropicolinate (0.085 g, 37%) as a white solid:¹H NMR (400 MHz, CDCl₃) δ 5.08 (s, 2H), 3.97 (s, 3H); ¹³C NMR (101 MHz,CDCl₃) δ 163.57 (s, C═O), 143.29 (d, J=258.1 Hz, C5), 141.73 (d, J=5.1Hz, C2), 141.05 (d, J=12.7 Hz, C4), 135.32 (d, J=16.8 Hz, C6), 116.26(s, C3), 53.24 (s, OMe); ¹⁹F NMR (376 MHz, CDCl₃) δ −135.63 (s).

Coupling

Example 6a Methyl4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate

A 250 mL three-neck flask with a reflux condenser, a nitrogen inlet anda thermocouple was charged with methyl4-amino-3,6-dichloro-5-fluoropicolinate (9.965 g, 41.7 mmol),2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (12.74 g, 52.1mmol) and KF (4.84 g, 83 mmol). Acetonitrile (78 mL) and water (26 mL)were added. The reaction mixture was purged with nitrogen.Dichlorobis(triphenylphosphine)palladium(II) (Pd(PPh₃)₂Cl₂; 1.477 g,2.10 mmol, 5 mol %) was added, and the solution was heated to 70° C.under nitrogen for 2 h. Upon cooling to room temperature, a precipitateformed which was filtered and washed with water. The precipitate wasdissolved in EtOAc (ca 500 mL) and washed with water and then brine. Theorganic layer was dried (MgSO₄) and the solvent was removed using arotary evaporator to give an orange solid, which was dried in vacuumoven at 50° C. (11.46 g, 76% yield): mp 169-170.5° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 7.48 (d, J=8.4 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.15 (s, 2H),3.96 (s, 3H), 3.90 (s, 3H); ¹³C{¹H} NMR (101 MHz, DMSO-d₆) δ 164.85 (s),153.11 (d, J=252.5 Hz), 146.29 (s), 144.52 (d, J=4.3 Hz), 143.74 (s),142.75 (dd, J=227.1, 14.0 Hz), 136.38 (d, J=13.4 Hz), 128.58 (d, J=3.2Hz), 125.87 (s), 125.54 (d, J=3.5 Hz), 122.89 (dd, J=13.8, 4.0 Hz),113.01 (d, J=3.0 Hz), 61.61 (d, J=4.2 Hz), 52.70 (s); ESIMS m/z 364([M+H]⁺). Anal. Calcd for C₁₄H₁₀Cl₂F₂N₂O₃: C, 46.30; H, 2.78; N, 7.71.Found: C, 46.60; H, 2.68; N, 7.51.

Example 6b4-Amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinonitrile

A mixture of 4-amino-3,6-dichloro-5-fluoropicolinonitrile (0.37 g, 1.80mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (0.549g, 2.24 mmol) and KF (0.209 g, 3.59 mmol) was taken into acetonitrile(6.75 mL) and water (2.25 mL). The mixture was stirred and sparged witha nitrogen atmosphere. Pd(PPh₃)₂Cl₂ (63 mg, 0.1 mmol) was added, and themixture was again sparged with nitrogen. The solution was then heated to75° C. under nitrogen for 2 h. Upon cooling down, a precipitate formedand was collected by filtration, washed with water and dried undervacuum to give the product (0.34 g) as an off-white solid. The aqueousphase was extracted with EtOAc (3×), and the combined organic extractswere washed with brine, dried, and concentrated. Purification by silicagel chromatography gave additional product (0.12 g) as a white solid.Total yield 78%. ¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (dd, J=8.5, 1.4 Hz,1H), 7.45 (s, 2H), 7.33 (dd, J=8.5, 7.2 Hz, 1H), 3.94 (s, 3H); ¹³C {¹H}NMR (101 MHz, DMSO-d₆) δ 152.97 (d, J=253.2 Hz), 145.73 (d, J=260.8 Hz),143.82 (d, J=13.7 Hz), 141.83 (d, J=14.7 Hz), 138.45 (d, J=14.8 Hz),133.93-132.79 (m), 128.93 (d, J=3.3 Hz), 127.74 (s), 126.37-125.10 (m),122.08 (dd, J=13.6, 3.9 Hz), 119.34 (d, J=4.5 Hz), 114.99 (s), 61.61(s); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −129.00 (dd, J=28.2, 7.0 Hz, 1F),−133.76 (d, J=28.2 Hz, 1F); ESIMS m/z 330.1 ([M+H]⁺).

What is claimed is:
 1. A process for the preparation of a4-amino-3-chloro-5-fluoro-6-(substituted)picolinate of the Formula I

wherein R represents C₁-C₄ alkyl, cyclopropyl, C₂-C₄ alkenyl or phenylsubstituted with from 1 to 4 substituents independently selected fromhalogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy;and R¹ represents C₁-C₁₂ alkyl or an unsubstituted or substituted C₇-C₁₁arylalkyl; which comprises the following steps: a) fluorinating3,4,5,6-tetrachloropicolinonitrile (Formula A)

with a source of fluoride ion to produce3-chloro-4,5,6-trifluoropicolinonitrile (Formula B)

b) aminating 3-chloro-4,5,6-trifluoropicolinonitrile (Formula B) withammonia to produce 4-amino-3-chloro-5,6-difluoropicolinonitrile (FormulaC)

c) reacting the fluoro substituent in the 6-position of4-amino-3-chloro-5,6-difluoropicolinonitrile (Formula C) with hydrazineto produce 4-amino-3-chloro-5-fluoro-6-hydrazinopicolinonitrile (FormulaD)

d) halogenating 4-amino-3-chloro-5-fluoro-6-hydrazinopicolinonitrile(Formula D) with a chlorine, bromine or iodine source to produce a4-amino-3-chloro-5-fluoro-6-halopicolinonitrile of Formula E

wherein L is Br, Cl or I; e) hydrolyzing and esterifying the4-amino-3-chloro-5-fluoro-6-halopicolinonitrile of Formula E with astrong acid and an alcohol (R¹OH) to produce a4-amino-3-chloro-5-fluoro-6-halopicolinate of Formula F

wherein L and R¹, are as previously defined; and f) coupling the4-amino-3-chloro-5-fluoro-6-halopicolinate of Formula F with an aryl,alkyl or alkenyl metal compound of the Formula GR-Met  G wherein R is as previously defined and Met represents,Zn-halide, Zn—R, tri-(C₁-C₄ alkyl)tin, copper, or B(OR²)(OR³), where R²and R³ are independent of one another, hydrogen, C₁-C₄ alkyl, or whentaken together form an ethylene or propylene group in the presence of atransition metal catalyst to produce the4-amino-3-chloro-5-fluoro-6-(substituted)picolinate of Formula I.
 2. Theprocess of claim 1 in which the coupling of step f) is performed priorto the hydrolysis and esterification of step e).
 3. An improved processof increasing the amount of recoverable3-chloro-4,5,6-trifluoropicolinonitrile (Formula B)

prepared from fluorinating 3,4,5,6-tetrachloropicolinonitrile (FormulaA)

with a source of fluoride ion wherein the improvement comprises thesteps of: i) isolating the over-fluorinated3,4,5,6-tetrafluoropicolinonitrile (H)

by-product from fluorinating 3,4,5,6-tetrachloropicolinonitrile; ii)reacting the isolated 3,4,5,6-tetrafluoropicolinonitrile (H) (a) withlithium chloride (LiCl), (b) with 3,4,5,6-tetrachloropicolinonitrile(Formula A) in the presence of a phase-transfer catalyst or (c) with acombination of LiCl and 3,4,5,6-tetrachloropicolinonitrile to produce amixture consisting predominantly of 3,4,5,6-tetrachloropicolinonitrile,monofluoro-trichloropicolinonitrile anddifluoro-dichloropicolinonitrile; and iii) recycling the mixtureconsisting predominantly of 3,4,5,6-tetrachloropicolinonitrile,monofluoro-trichloropicolinonitrile anddifluoro-dichloropicolinonitriles to the fluorination reaction preparing3-chloro-4,5,6-trifluoropicolinonitrile (Formula B).